The following description provides a summary of information relevant to the present disclosure and is not an admission that any of the information provided or publications referenced herein is prior art to the present disclosure.
The innate immune system of humans and animals is known to have an anti-cancer response. Some tumor cells express antigens which are recognized by the immune system such as mutated gene products (P. van der Bruggen et al., Immunological Rev., 188:51-64, 2002). Treatments such as adoptive immunotherapy or immunomodulators such as cytokines have resulted in tumor regression (S. Antonia et al., Current Opinion in Immunol., 16:130-136, 2004; S. Rosenberg, Cancer J. Sci. Am., 6(S):2, 2000). However, these types of immunotherapies haven't proven broadly effective at eradicating tumor cells. It is thought that immunosuppressive responses in the microenvironment of the tumor, poor antigen recognition on tumor cells, and a lack of co-stimulatory signaling molecules are responsible for the poor performance. As a result, molecules which generate co-stimulatory responses have become desirable for therapies aimed at enhancing anti-tumor immune response.
T cell activation and response is a complex process that requires both antigen-specific T cell receptor engagement as well as other co-stimulatory signals. These co-stimulatory signals can have different functions such as simply enhancing the initial T cell receptor activation, promoting T cell proliferation, inducing cytokine production, or cytotoxicity. There are many different receptors considered co-stimulatory. The tumor-necrosis factor receptor superfamily is one of two main groups of co-stimulatory receptors and 4-1BB(CD 137) is a member of this superfamily. Proteins in this family are involved in the regulation of cell proliferation, differentiation, and programmed cell death.
4-1BB is a type I membrane glycoprotein that was initially described in mice (B. Kwon et al., P.N.A.S. USA, 86:1963-1967, 1989) and is a 30 kDa type I membrane glycoprotein expressed as 55 kDa homodimer. It has also been identified in humans (M. Alderson et al., Eur. J. Immunol., 24:2219-2227, 1994) and the two forms are 60% identical at the amino acid level. 4-1BB is mainly found on lymphoid originating cells such as Natural Killer (NK), NKT-cells, activated T cells, CD4CD25 regulatory T-cells, activated thymocytes, and intraepithelial lymphocytes. It has also been found on dendritic cells, neutrophils, and eosinophils.
4-1BB is expressed on active CD4+ and CD8+ T-cells, but has a much stronger co-stimulatory effect on CD8+ T-cells in vivo (M. Croft, Nat. Rev. Immunol., 3:609-620, 2003). Both expression of 4-1BB ligand in tumor cells and administration of agonistic 4-1BB antibodies have been demonstrated to provide enhanced tumor immunity in mice (S. Mogi et al. 2000. Immunology, 101:541-547, 2003; E. Kocak et al., Cancer Res., 66:7276-7284, 2006). Altogether, 4-1BB stimulation results in enhanced expansion, survival, and effector functions of newly primed CD8+ T-cells, acting, in part, directly on these cells. Based on the critical role of 4-1BB stimulation in CD8+ T-cell function and survival, manipulation of the 4-1BB/4-1BBL system provides a plausible approach for the treatment of tumors and viral pathogens.
In addition to its role in the development of immunity to cancer, experimental data supports the use of 4-1BB agonistic antibodies for the treatment of autoimmune and viral diseases (B. Kwon et al., Exp. Mol. Med., 35(1):8-16, 2003; H. Salih et al., J. Immunol., 167(7):4059-4066; 2001; E. Kwon et al., P.N.A.S. USA, 96:15074-15079, 1999; J. Foell et al., N.Y. Acad. Sci., 987:230-235, 2003; Y. Sun et al., Nat. Med., 8(12):1405-1413, 2002; S. K. Seo et al., Nat. Med., 10:1099-1094, 2004).
Given the variety of important roles 4-1BB has in effecting immune response, generating molecules which bind this receptor and compete with its cognate ligand 4-1BBL represent an important potential therapeutic approach for a variety of human diseases such as cancer, autoimmune disease, and infectious disease. Given the strong interest in generating antibodies to this target, producing high affinity aptamers to this target is an important alternative. Aptamers can be more easily produced, more reproducibly manufactured, and are significantly cheaper.